Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A great deal of the energy and time of a cell is invested in DNA repair activities. The first step in DNA repair pathways is recognition of the lesion on the DNA. The classical lesion-recognizing proteins interact with other repair proteins to form multiprotein complexes most notable of which are those that function in Nucleotide Excision Repair (NER). Proteins involved in lesion recognition include HMG1 and 2 recognizing cisplatin adducts but also maintaining active nucleosome structures and interacting with loops in cruciforms; HMG-box nuclear proteins; XPA and XPC lacking in xeroderma pigmentosum patients and involved in lesion recognition during NER; p53 recognizing strand breaks and insertion/deletion mismatches and causing arrest in the cell cycle; MSH2 mismatch repair protein identified as the human colon cancer gene product; and others including the transcription factor YB-1 that binds to depurinated DNA with a higher affinity compared with undamaged DNA. Other type of lesion-recognizing proteins are also repair enzymes like the O(6)-methylguanine-DNA methyltransferase and DNA glycosylases. Lesion recognition is an important process and might be the rate-limiting step in the overall repair process.
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PMID:DNA lesion-recognizing proteins and the p53 connection. 861 13

Hypermutation of immunoglobulin genes is a key process in antibody diversification. Little is known about the mechanism, but the availability of rapid facile assays for monitoring immunoglobulin hypermutation would greatly aid the development of culture systems for hypermutating B cells as well as the screening for individuals deficient in the process. Here we describe two such assays. The first exploits the non-randomness of hypermutation. The existence of a mutational hotspot in the Ser31 codon of a transgenic immunoglobulin V gene allowed us to use PCR to detect transgene hypermutation and identify cell populations in which this mutation had occurred. For animals that do not carry immunoglobulin transgenes, we exploited the fact that hypermutation extends into the region flanking the 3'-side of the rearranged J segments. We show that PCR amplification of the 3'-flank of VDJH rearrangements that involve members of the abundantly-used VHJ558 family provides a large database of mutations where the germline counterpart is unequivocally known. This assay was particularly useful for analysing endogenous immunoglobulin gene hypermutation in several mouse strains. As a rapid assay for monitoring mutation in the JH flanking region, we show that one can exploit the fact that, following denaturation/renaturation, the PCR amplified JH flanking region DNA from germinal centre B cells yields mismatched heteroduplexes which can be quantified in a filter binding assay using the bacterial mismatch repair protein MutS -Wagner et al. (1995) Nucleic Acids Res. 23, 3944-3948-. Such assays enabled us, by example, to show that antibody hypermutation proceeds in the absence of the p53 tumour suppressor gene product.
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PMID:Rapid methods for the analysis of immunoglobulin gene hypermutation: application to transgenic and gene targeted mice. 911 57

To examine the etiological association of genetic instability in lung tumorigenesis, we investigated the frequency of microsatellite instability (MI) of eight dinucleotide repeat markers in 68 patients with non-small cell lung cancer. Twenty-eight patients (41.2%) evidenced instability in multiple tested microsatellite markers ranging from 3-7 and were defined as MI-positive patients. MI occurred more frequently in patients suffering from squamous cell lung carcinoma (P = 0.004). We examined the association between MI and expression of hMLH1 mismatch repair protein by immunohistochemical analysis of hMLH1 protein in paraffin-embedded tumors from 64 patients. Twenty MI-positive patients (76.9%) had no expression of hMLH1 protein. The data showed that MI was associated with altered hMLH1 expression (P = 0.03). To examine the role of genetic instability in the previous identified small intragenic deletion of the p53 gene, we explored the association between MI and p53 gene mutations. All patients, except one, containing small intragenic deletion in p53 gene showed MI (P = 0.018). In addition, we found that MI was not associated with the prognosis. Our data suggest that MI plays a significant role in non-small cell lung cancer tumorigenesis in Taiwan and that MI is associated with the altered expression of hMLH1 mismatch repair protein. In addition, MI may be involved in frequent small intragenic deletions of p53 gene.
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PMID:Correlation of genetic instability with mismatch repair protein expression and p53 mutations in non-small cell lung cancer. 1081 81

The contributions of defective mismatch repair and mutated p53 to cisplatin resistance of human tumor cells were analysed. Mismatch repair defects were not associated with a predictable degree of resistance among several tumor cell lines. Repair defective variants of the A2780 ovarian carcinoma cell line which were isolated by selection for a methylation tolerant phenotype and did not express the hMLH1 mismatch repair protein, were highly resistant to cisplatin. Their cisplatin resistance was not a simple consequence of the mismatch repair defect. They were members of a drug-naive subpopulation of A2780 in which a silent hMLH1 gene accompanies a mutated p53. Two complementary approaches indicated that each defect contributes to cisplatin resistance independently and to a different extent. Firstly, separate introduction of a p53 defect into A2780 cells significantly increased their cisplatin resistance; defective hMLH1 provided less extensive protection. Secondly, azadeoxycytidine reactivation of the silent hMLH1 gene or expression of a transfected hMLH1 cDNA sensitized the doubly hMLH1/p53 deficient cells only slightly to cisplatin. Both approaches indicate that defective p53 status is a major determinant of cisplatin resistance and defective mismatch repair is a minor, and independent, contributor. The data have implications for the development of intrinsic cisplatin resistance.
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PMID:Spontaneous development of drug resistance: mismatch repair and p53 defects in resistance to cisplatin in human tumor cells. 1091 68

Molecular analysis of hereditary nonpolyposis colorectal carcinomas (HNPCC) has identified DNA mismatch repair deficiencies with resulting microsatellite instability (MSI) as a pathway of carcinogenesis that appears to be relevant for prognosis, treatment, and possibly prevention. In this study, expression of cell cycle proteins and other known prognostic markers is correlated with the microsatellite status of colorectal cancers (CRC). One hundred consecutive cases from the CRC Registry at Thomas Jefferson University were analyzed for MSI. Immunohistochemistry was performed for the mismatch repair proteins hMLH1 and hMSH2, tumor suppressor p53, apoptosis inhibitor bcl-2, cell cycle proteins p21(WAF1/CIP1), and p27 and the proliferation markers Ki-67 and topoisomerase II. High MSI (MSI-H) is significantly correlated with loss of either hMLH1 or hMSH2, presence of bcl-2, and absence of p53. p21(WAF1/CIP1) is positive in all tumors with MSI-H. Previous findings of a lower proliferation rate were confirmed with a topoisomerase II stain. Microsatellite stable (MSS) tumors generally express both MSH2 and MLH1. Other highly significant differences are positive p53 in 56% of MSS cases and negative bcl-2 in 98% of MSS cases. p27 expression is found in approximately 50% of all CRCs irrespective of the microsatellite status. MSI-H tumors follow the mutator pathway, with loss of expression of one mismatch repair protein, wild-type p53, lower proliferation, and positivity for p21(WAF1/CIP1). MSS tumors follow the suppressor pathway, characterized by p53 overexpression, higher proliferation, and absence of bcl-2 expression; p21(WAF1/CIP1) expression can be variable. These data provide a molecular basis for the clinical observation that patients with HNPCC appear to have a more favorable prognosis. HUM PATHOL 31:1506-1514.
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PMID:Colorectal carcinomas with high microsatellite instability: defining a distinct immunologic and molecular entity with respect to prognostic markers. 1115 Mar 76

It has been hypothesized that the degradation of the largest subunit of RNA polymerase II (polIILS) is required for transcription-coupled repair (TCR) of UV light-induced transcription-blocking lesions. In this study we further investigated the mechanism of UV-induced degradation of polIILS using cell lines with specific defects in TCR or in the recovery of RNA synthesis. It was found that the hypophosphorylated IIa form of polIILS rapidly decreased following UV-irradiation in all cell lines tested. Inhibition of proteasome activity resulted in an increase of the hyperphosphorylated IIo form of polIILS in UV-irradiated cells, while inhibition of CTD-kinases resulted in the retention of the IIa form. In UV-irradiated Cockayne's syndrome cells, which are defective in TCR, the levels of the IIo form increased in a similar manner as when proteasome inhibitors were added to UV-irradiated normal cells. In contrast, TCR-deficient HCT116 cells, which lack the mismatch repair protein MLH1, showed proficient degradation of polIILS as did cells with deficiencies in the recovery of RNA synthesis following UV-irradiation due to defective p53. Furthermore, we found that proteasome function was important for the recovery of mRNA synthesis even in TCR-deficient HCT116 cells. Our results suggest that proteasome-mediated degradation of polIILS is preceded by phosphorylation of the C-terminal domain of polIILS and requires the CS-A and CS-B but not MLH1 or p53 proteins. Furthermore, our results suggest that following UV-irradiation, the degradation of polIILS is required for the efficient recovery of mRNA synthesis but not for TCR per se.
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PMID:UV light-induced degradation of RNA polymerase II is dependent on the Cockayne's syndrome A and B proteins but not p53 or MLH1. 1118 41

The human lymphoblastoid cell, TK6, exhibited a dose-dependent cytotoxic and apoptotic response following treatment with the food borne heterocyclic amine, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). Augmentation of the p53 protein and increases in p21-WAF1 levels were also observed. Comparison of the survival by clonogenic assays and the percentage of apoptotic cells (cells containing subG1 DNA or condensed nuclei) revealed that only 10-20% of the PhIP-induced cell death could be attributed to apoptosis that occurred in the first 24h after treatment. MT1, a derivative of TK6 that contains mutations in both alleles of its hMSH6 gene and is mismatch repair deficient, showed a decreased apoptotic response. A significant increase (P<0.05) in apoptosis was observed in TK6 and not in MT1 following treatment with 2.5microg/ml PhIP. A five- to six-fold increase and less than a two-fold increase in the fraction of apoptotic cells were observed in TK6 and MT1, respectively. Treatment with 5microg/ml PhIP resulted in significant increases in apoptosis (P<0.05) in TK6 and MT1. The percentages of apoptotic cells were, however, two- to three-fold higher in TK6 than in MT1. HCT116, a hMLH1 defective mismatch repair deficient colorectal carcinoma cell line, also exhibited lower PhIP-induced apoptosis than its mismatch repair proficient chromosome transfer cell line (HCT116+chr3) following PhIP treatment. These results show that PhIP-induced apoptosis is mediated through a mismatch repair dependent pathway. Accumulation of p53 in TK6 and MT1 were evident in samples taken 24h after PhIP treatment. Increases in p21-WAF1 were also observed in both cell lines confirming that the p53 was functional. The lower apoptotic response of MT1 but similar p53 accumulation in TK6 and MT1 suggest that the mismatch repair protein(s) are involved downstream of p53 or that PhIP-induced apoptosis is p53-independent.
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PMID:Heterocyclic amine induced apoptotic response in the human lymphoblastoid cell line TK6 is linked to mismatch repair status. 1142 20

The ability of the tumor suppressor protein, p53, to recognize certain types of DNA lesions may represent one of the mechanisms by which this protein modulates cellular response to DNA damage. p53 DNA binding properties are regulated by several factors, such as post-translational modifications including phosphorylation and acetylation, regulation by its own C-terminal domain and interactions with other cellular proteins. Substrates resembling Holliday junctions and extra base bulges were used to study the effect of three nuclear proteins, HMG-1, HMG I(Y) and hMSH2-hMSH6, on the lesion binding properties of p53. Gel retardation assays revealed that the three proteins had varying effects on p53 binding to these substrates. HMG-1 did not influence p53 binding to Holliday junctions or 3-cytosine bulges. HMG I(Y) rapidly dissociated p53 complexes with Holliday junctions but not 3-cytosine bulges. Finally, the mismatch repair protein complex, hMSH2-hMSH6, enhanced p53 binding to both substrates by 3-4-fold. Together, these results demonstrate that p53 DNA binding activity is highly influenced by the presence of other proteins, some having a dominant effect while others have a negative effect.
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PMID:Interactions between p53, hMSH2-hMSH6 and HMG I(Y) on Holliday junctions and bulged bases. 1203 30

Our previous recombination and biochemical analyses have led to the hypothesis that the tumor suppressor p53 monitors homologous recombination, a function which was previously attributed to the mismatch repair protein MSH2. Here, we show that a certain fraction of p53 is concentrated within discrete nuclear foci of cells synchronized in G1 phase, a pattern which becomes even more pronounced in S phase, especially after gamma-ray treatment. p53 foci show some colocalization with MSH2 within distinct foci during G1 phase, while dots formed by BRCA1 display an independent localization pattern. In S phase nuclei, p53 foci almost completely colocalize with MSH2 foci and associate with the recombination surveillance factor BRCA1 in irradiated S phase cells. These p53 and MSH2 foci also show significant overlaps with foci of the recombination enzymes Rad50 and Rad51, which for the first time unveiled recombination-related functions of p53 in replicating cells. During S phase, p53 and MSH2 are maximally active in binding to early recombination intermediates, and coexist within the same nuclear DNA-protein complexes. Our data suggest that p53 is linked similarly to homologous recombination as MSH2 and provide further evidence for the new concept of a dual role of p53 in the regulation of growth and repair.
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PMID:Association of p53 and MSH2 with recombinative repair complexes during S phase. 1210 17

The Fragile Histidine Triad gene, encompassing the FRA3B fragile site at chromosome 3p14.2, is a candidate tumour suppressor gene involved in multiple tumour types including colorectal carcinomas. Recently, it has been reported that the Fragile Histidine Triad gene may be a target of damage in a fraction of mismatch deficient tumours. To explore this hypothesis, we analysed both Fragile histidine triad and mismatch repair protein (Msh2 and Mlh1) expression using immumohistochemical methods in 52 advanced colorectal carcinomas (19 well-, 17 moderately-, and 16 poorly-differentiated). In addition, we examined whether the Fragile histidine triad and mismatch repair protein expression correlated with p53 expression and clinicopathological findings. Significant loss or reduction of Fragile histidine triad expression was noted in 18 of the 52 (34.6%) advanced colorectal carcinomas: 2 (10.5%) well-differentiated, 3 (17.6%) moderately-differentiated, 13 (81.3%) poorly-differentiated carcinomas, the frequency being significantly higher in the latter than that in the former two (P<0.0001). Loss of mismatch repair protein (mainly, Mlh1) expression was detected in 21 of the 52 (40.4%) colorectal carcinomas. Moreover, reduced Fragile histidine triad expression was significantly associated with absence of mismatch repair protein expression in the advanced colorectal carcinomas (P<0.0001). However, the Fragile histidine triad and mismatch repair protein expression was not significantly associated with p53 expression. These results suggested that reduced Fragile histidine triad expression might be correlated with mismatch repair expression, but not with p53 expression.
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PMID:Reduced Fhit expression is associated with mismatch repair deficiency in human advanced colorectal carcinoma. 1217 81


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